Abstract
Micturition requires precise control of bladder and urethral sphincter via parasympathetic, sympathetic and somatic motoneurons. This involves a spino-bulbospinal control circuit incorporating Barrington's nucleus in the pons (Barr). Ponto-spinal glutamatergic neurons that express corticotrophin-releasing hormone (CRH) form one of the largest Barr cell populations. BarrCRH neurons can generate bladder contractions, but it is unknown whether they act as a simple switch or provide a high-fidelity pre-parasympathetic motor drive and whether their activation can actually trigger voids. Combined opto- and chemo-genetic manipulations along with multisite extracellular recordings in urethane anaesthetised CRHCre mice show that BarrCRH neurons provide a probabilistic drive that generates co-ordinated voids or non-voiding contractions depending on the phase of the micturition cycle. CRH itself provides negative feedback regulation of this process. These findings inform a new inferential model of autonomous micturition and emphasise the importance of the state of the spinal gating circuit in the generation of voiding.
Highlights
The regulated production, storage and elimination of liquid waste as urine plays a critical homeostatic role in maintaining the health of organisms
Tonic unilateral activation of BarrCRH neurons (5–20 Hz x 20 ms, 465 nm light pulses, applied for three completed voiding cycles) produced an increase of micturition frequency manifesting as a significant shortening in inter-void interval associated with a reduction of the threshold pressure for voiding (84.0 ± 4.7% at 10 Hz, Figure 1E)
Chemogenetic inhibition caused a prolongation of the latency to void. This effectively produced a period of urinary retention, that persisted for 2 hr (Figure 2E). These findings indicate that BarrCRH neurons have a potent ability to modulate the autonomous micturition cycle and that their basal level of activity is of functional importance
Summary
The regulated production, storage and elimination of liquid waste as urine (micturition) plays a critical homeostatic role in maintaining the health of organisms. A common technical limitation of these pontine neural recordings is the difficulty of identifying specific cell populations during or after recordings This has been addressed for populations of Barrington’s neurons through fibre-photometry of genetically encoded calcium indicators in mice (Hou et al, 2016; Keller et al, 2018; Yao et al, 2018) to show that BarrCRH and BarrESR1 neuronal activity increases around the time of voiding/scent marking respectively. We study the role of BarrCRH neurons in the autonomous micturition cycle in anaesthetised mice using opto- and chemo-genetic interventions as well as recordings of the firing activity of identified BarrCRH neurons in vivo This has informed the development of a model indicating that these BarrCRH neurons provide a probabilistic signal to spinal circuits that is gated to trigger either nonvoiding bladder contractions, which enable inferences to be made about the degree of bladder fullness, or voiding if a threshold level of pressure has been reached
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